Analyte sensor sensitivity attenuation mitigation

ABSTRACT

Method and apparatus for receiving a first signal from a first working electrode of a glucose sensor positioned at a first predetermined position under the skin layer, receiving a second signal from a second working electrode of the glucose sensor positioned at a second predetermined position under the skin layer, the second signal received substantially contemporaneous to receiving the first signal, detecting a dropout in the signal level associated with one of the first or second signals, comparing the first signal and the second signal to determine a variation between the first and second signals, and confirming one of the first or second signals as a valid glucose sensor signal output when the determined variation between the first and the second signals is less than a predetermined threshold level are provided.

BACKGROUND

The detection of the level of analytes, such as glucose, lactate,oxygen, and the like, in certain individuals is vitally important totheir health. For example, the monitoring of glucose is particularlyimportant to individuals with diabetes. Diabetics may need to monitorglucose levels to determine when insulin is needed to reduce glucoselevels in their bodies or when additional glucose is needed to raise thelevel of glucose in their bodies.

Accordingly, of interest are devices that allow a user to test for oneor more analytes.

OVERVIEW

In accordance with the various embodiments of the present disclosure,method, device and system for receiving a first signal from a firstworking electrode of a glucose sensor positioned at a firstpredetermined position under the skin layer, receiving a second signalfrom a second working electrode of the glucose sensor positioned at asecond predetermined position under the skin layer, the second signalreceived substantially contemporaneous to receiving the first signal,detecting a dropout in the signal level associated with one of the firstor second signals, comparing the first signal and the second signal todetermine a variation between the first and second signals, andconfirming one of the first or second signals as a valid glucose sensorsignal output when the determined variation between the first and thesecond signals is less than a predetermined threshold level areprovided.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a block diagram of an embodiment of a data monitoring andmanagement system according to the present disclosure;

FIG. 2 shows a block diagram of an embodiment of the transmitter unit ofthe data monitoring and management system of FIG. 1;

FIG. 3 shows a block diagram of an embodiment of the receiver/monitorunit of the data monitoring and management system of FIG. 1;

FIG. 4 shows a schematic diagram of an embodiment of an analyte sensoraccording to the present disclosure;

FIGS. 5A-5B show a perspective view and a cross sectional view,respectively of another embodiment of an analyte sensor;

FIG. 6 is a graphical illustration of sensor sensitivity attenuationmitigation using multiple working electrodes in accordance with oneaspect of the present disclosure;

FIG. 7 is a graphical illustration of sensor sensitivity attenuationmitigation using multiple working electrodes in accordance with anotheraspect of the present disclosure;

FIGS. 8A-8C are embodiments of analyte sensor electrode geometry forsensitivity attenuation mitigation in accordance with aspects of thepresent disclosure; and

FIGS. 9A-9B are embodiments of analyte sensor electrode geometry forsensitivity attenuation mitigation in accordance with further aspects ofthe present disclosure.

DETAILED DESCRIPTION

Before the present disclosure is described, it is to be understood thatthis disclosure is not limited to particular embodiments described, assuch may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting, since the scope ofthe present disclosure will be limited only by the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the disclosure. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges as also encompassed within the disclosure, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the disclosure.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentdisclosure.

The figures shown herein are not necessarily drawn to scale, with somecomponents and features being exaggerated for clarity.

Generally, embodiments of the present disclosure relate to methods anddevices for detecting at least one analyte such as glucose in bodyfluid. Embodiments relate to the continuous and/or automatic in vivomonitoring of the level of one or more analytes using a continuousanalyte monitoring system that includes an analyte sensor at least aportion of which is to be positioned beneath a skin surface of a userfor a period of time and/or the discrete monitoring of one or moreanalytes using an in vitro blood glucose (“BG”) meter and an analytetest strip. Embodiments include combined or combinable devices, systemsand methods and/or transferring data between an in vivo continuoussystem and a BG meter system.

Accordingly, embodiments include analyte monitoring devices and systemsthat include an analyte sensor—at least a portion of which ispositionable beneath the skin of the user—for the in vivo detection, ofan analyte, such as glucose, lactate, and the like, in a body fluid.Embodiments include wholly implantable analyte sensors and analytesensors in which only a portion of the sensor is positioned under theskin and a portion of the sensor resides above the skin, e.g., forcontact to a transmitter, receiver, transceiver, processor, etc. Thesensor may be, for example, subcutaneously positionable in a patient forthe continuous or periodic monitoring of a level of an analyte in apatient's interstitial fluid. For the purposes of this description,continuous monitoring and periodic monitoring will be usedinterchangeably, unless noted otherwise. The sensor response may becorrelated and/or converted to analyte levels in blood or other fluids.In certain embodiments, an analyte sensor may be positioned in contactwith interstitial fluid to detect the level of glucose, in whichdetected glucose may be used to infer the glucose level in the patient'sbloodstream. Analyte sensors may be insertable into a vein, artery, orother portion of the body containing fluid. Embodiments of the analytesensors of the subject disclosure may be configured for monitoring thelevel of the analyte over a time period which may range from minutes,hours, days, weeks, or longer.

Of interest are analyte sensors, such as glucose sensors, that arecapable of in vivo detection of an analyte for about one hour or more,e.g., about a few hours or more, e.g., about a few days of more, e.g.,about three or more days, e.g., about five days or more, e.g., aboutseven days or more, e.g., about several weeks or at least one month.Future analyte levels may be predicted based on information obtained,e.g., the current analyte level at time t₀, the rate of change of theanalyte, etc. Predictive alarms may notify the user of a predictedanalyte level that may be of concern in advance of the user's analytelevel reaching the future level. This provides the user an opportunityto take corrective action.

FIG. 1 shows a data monitoring and management system such as, forexample, an analyte (e.g., glucose) monitoring system 100 in accordancewith certain embodiments. Embodiments of the subject disclosure arefurther described primarily with respect to glucose monitoring devicesand systems, and methods of glucose detection, for convenience only andsuch description is in no way intended to limit the scope of thedisclosure. It is to be understood that the analyte monitoring systemmay be configured to monitor a variety of analytes at the same time orat different times.

Analytes that may be monitored include, but are not limited to, acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin,creatine kinase (e.g., CK-MB), creatine, creatinine, DNA, fructosamine,glucose, glutamine, growth hormones, hormones, ketone bodies, lactate,peroxide, prostate-specific antigen, prothrombin, RNA, thyroidstimulating hormone, and troponin. The concentration of drugs, such as,for example, antibiotics (e.g., gentamicin, vancomycin, and the like),digitoxin, digoxin, drugs of abuse, theophylline, and warfarin, may alsobe monitored. In those embodiments that monitor more than one analyte,the analytes may be monitored at the same or different times.

The analyte monitoring system 100 includes a sensor 101, a dataprocessing unit 102 connectable to the sensor 101, and a primaryreceiver unit 104 which is configured to communicate with the dataprocessing unit 102 via a communication link 103. In certainembodiments, the primary receiver unit 104 may be further configured totransmit data to a data processing terminal 105 to evaluate or otherwiseprocess or format data received by the primary receiver unit 104. Thedata processing terminal 105 may be configured to receive data directlyfrom the data processing unit 102 via a communication link which mayoptionally be configured for bi-directional communication. Further, thedata processing unit 102 may include a transmitter or a transceiver totransmit and/or receive data to and/or from the primary receiver unit104 and/or the data processing terminal 105 and/or optionally thesecondary receiver unit 106.

Also shown in FIG. 1 is an optional secondary receiver unit 106 which isoperatively coupled to the communication link and configured to receivedata transmitted from the data processing unit 102. The secondaryreceiver unit 106 may be configured to communicate with the primaryreceiver unit 104, as well as the data processing terminal 105. Thesecondary receiver unit 106 may be configured for bi-directionalwireless communication with each of the primary receiver unit 104 andthe data processing terminal 105. As discussed in further detail below,in certain embodiments the secondary receiver unit 106 may be ade-featured receiver as compared to the primary receiver, i.e., thesecondary receiver may include a limited or minimal number of functionsand features as compared with the primary receiver unit 104. As such,the secondary receiver unit 106 may include a smaller (in one or more,including all, dimensions), compact housing or embodied in a device suchas a wrist watch, arm band, etc., for example. Alternatively, thesecondary receiver unit 106 may be configured with the same orsubstantially similar functions and features as the primary receiverunit 104. The secondary receiver unit 106 may include a docking portionto be mated with a docking cradle unit for placement by, e.g., thebedside for night time monitoring, and/or a bi-directional communicationdevice. A docking cradle may recharge a powers supply.

Only one sensor 101, data processing unit 102 and data processingterminal 105 are shown in the embodiment of the analyte monitoringsystem 100 illustrated in FIG. 1. However, it will be appreciated by oneof ordinary skill in the art that the analyte monitoring system 100 mayinclude more than one sensor 101 and/or more than one data processingunit 102, and/or more than one data processing terminal 105. Multiplesensors may be positioned in a patient for analyte monitoring at thesame or different times. In certain embodiments, analyte informationobtained by a first positioned sensor may be employed as a comparison toanalyte information obtained by a second sensor. This may be useful toconfirm or validate analyte information obtained from one or both of thesensors. Such redundancy may be useful if analyte information iscontemplated in critical therapy-related decisions. In certainembodiments, a first sensor may be used to calibrate a second sensor.

The analyte monitoring system 100 may be a continuous monitoring system,or semi-continuous, or a discrete monitoring system. In amulti-component environment, each component may be configured to beuniquely identified by one or more of the other components in the systemso that communication conflict may be readily resolved between thevarious components within the analyte monitoring system 100. Forexample, unique IDs, communication channels, and the like, may be used.

In certain embodiments, the sensor 101 is physically positioned in or onthe body of a user whose analyte level is being monitored. The sensor101 may be configured to at least periodically sample the analyte levelof the user and convert the sampled analyte level into a correspondingsignal for transmission by the data processing unit 102. The dataprocessing unit 102 is coupleable to the sensor 101 so that both devicesare positioned in or on the user's body, with at least a portion of theanalyte sensor 101 positioned transcutaneously. The data processing unitmay include a fixation element such as adhesive or the like to secure itto the user's body. A mount (not shown) attachable to the user andmateable with the unit 102 may be used. For example, a mount may includean adhesive surface. The data processing unit 102 performs dataprocessing functions, where such functions may include but are notlimited to, filtering and encoding of data signals, each of whichcorresponds to a sampled analyte level of the user, for transmission tothe primary receiver unit 104 via the communication link 103. In oneembodiment, the sensor 101 or the data processing unit 102 or a combinedsensor/data processing unit may be wholly implantable under the skinlayer of the user.

In certain embodiments, the primary receiver unit 104 may include ananalog interface section including an RF receiver and an antenna that isconfigured to communicate with the data processing unit 102 via thecommunication link 103, and a data processing section for processing thereceived data from the data processing unit 102 such as data decoding,error detection and correction, data clock generation, data bitrecovery, etc., or any combination thereof.

In operation, the primary receiver unit 104 in certain embodiments isconfigured to synchronize with the data processing unit 102 to uniquelyidentify the data processing unit 102, based on, for example, anidentification information of the data processing unit 102, andthereafter, to periodically receive signals transmitted from the dataprocessing unit 102 associated with the monitored analyte levelsdetected by the sensor 101.

Referring again to FIG. 1, the data processing terminal 105 may includea personal computer, a portable computer such as a laptop or a handhelddevice (e.g., personal digital assistants (PDAs), telephone such as acellular phone (e.g., a multimedia and Internet-enabled mobile phonesuch as an iPhone or similar phone), mp3 player, pager, and the like),drug delivery device, each of which may be configured for datacommunication with the receiver via a wired or a wireless connection.Additionally, the data processing terminal 105 may further be connectedto a data network (not shown) for storing, retrieving, updating, and/oranalyzing data corresponding to the detected analyte level of the user.

The data processing terminal 105 may include an infusion device such asan insulin infusion pump or the like, which may be configured toadminister insulin to patients, and which may be configured tocommunicate with the primary receiver unit 104 for receiving, amongothers, the measured analyte level. Alternatively, the primary receiverunit 104 may be configured to integrate an infusion device therein sothat the primary receiver unit 104 is configured to administer insulin(or other appropriate drug) therapy to patients, for example, foradministering and modifying basal profiles, as well as for determiningappropriate boluses for administration based on, among others, thedetected analyte levels received from the data processing unit 102. Aninfusion device may be an external device or an internal device (whollyimplantable in a user).

In certain embodiments, the data processing terminal 105, which mayinclude an insulin pump, may be configured to receive the analytesignals from the data processing unit 102, and thus, incorporate thefunctions of the primary receiver unit 104 including data processing formanaging the patient's insulin therapy and analyte monitoring. Incertain embodiments, the communication link 103 as well as one or moreof the other communication interfaces shown in FIG. 1, may use one ormore of: an RF communication protocol, an infrared communicationprotocol, a Bluetooth® enabled communication protocol, an 802.11xwireless communication protocol, or an equivalent wireless communicationprotocol which would allow secure, wireless communication of severalunits (for example, per HIPAA requirements), while avoiding potentialdata collision and interference.

FIG. 2 shows a block diagram of an embodiment of a data processing unitof the data monitoring and detection system shown in FIG. 1. User inputand/or interface components may be included or a data processing unitmay be free of user input and/or interface components. In certainembodiments, one or more application-specific integrated circuits (ASIC)may be used to implement one or more functions or routines associatedwith the operations of the data processing unit (and/or receiver unit)using for example one or more state machines and buffers.

As can be seen in the embodiment of FIG. 2, the sensor 101 (FIG. 1)includes four contacts, three of which are electrodes—work electrode (W)210, reference electrode (R) 212, and counter electrode (C) 213, eachoperatively coupled to the analog interface 201 of the data processingunit 102. This embodiment also shows optional guard contact (G) 211.Fewer or greater electrodes may be employed. For example, the counterand reference electrode functions may be served by a singlecounter/reference electrode, there may be more than one workingelectrode and/or reference electrode and/or counter electrode, etc.

FIG. 3 is a block diagram of an embodiment of a receiver/monitor unitsuch as the primary receiver unit 104 of the data monitoring andmanagement system shown in FIG. 1. The primary receiver unit 104includes one or more of: a blood glucose test strip interface 301, an RFreceiver 302, an input 303, a temperature detection section 304, and aclock 305, each of which is operatively coupled to a processing andstorage section 307. The primary receiver unit 104 also includes a powersupply 306 operatively coupled to a power conversion and monitoringsection 308. Further, the power conversion and monitoring section 308 isalso coupled to the receiver processor 307. Moreover, also shown are areceiver serial communication section 309, and an output 310, eachoperatively coupled to the processing and storage unit 307. The receivermay include user input and/or interface components or may be free ofuser input and/or interface components.

In certain embodiments, the test strip interface 301 includes a glucoselevel testing portion to receive a blood (or other body fluid sample)glucose test or information related thereto. For example, the interfacemay include a test strip port to receive a glucose test strip. Thedevice may determine the glucose level of the test strip, and optionallydisplay (or otherwise notice) the glucose level on the output 310 of theprimary receiver unit 104. Any suitable test strip may be employed,e.g., test strips that only require a very small amount (e.g., onemicroliter or less, e.g., 0.5 microliter or less, e.g., 0.1 microliteror less), of applied sample to the strip in order to obtain accurateglucose information, e.g. FreeStyle® blood glucose test strips fromAbbott Diabetes Care Inc. Glucose information obtained by the in vitroglucose testing device may be used for a variety of purposes,computations, etc. For example, the information may be used to calibratesensor 101, confirm results of the sensor 101 to increase the confidencethereof (e.g., in instances in which information obtained by sensor 101is employed in therapy related decisions), etc.

In further embodiments, the data processing unit 102 and/or the primaryreceiver unit 104 and/or the secondary receiver unit 106, and/or thedata processing terminal/infusion section 105 may be configured toreceive the blood glucose value wirelessly over a communication linkfrom, for example, a blood glucose meter. In further embodiments, a usermanipulating or using the analyte monitoring system 100 (FIG. 1) maymanually input the blood glucose value using, for example, a userinterface (for example, a keyboard, keypad, voice commands, and thelike) incorporated in the one or more of the data processing unit 102,the primary receiver unit 104, secondary receiver unit 106, or the dataprocessing terminal/infusion section 105.

Additional detailed descriptions are provided in U.S. Pat. Nos.5,262,035; 5,264,104; 5,262,305; 5,320,715; 5,593,852; 6,175,752;6,650,471; 6,746, 582; 7,299,082, and in application Ser. No. 10/745,878filed Dec. 26, 2003, now U.S. Pat. No. 7,811,231, entitled “ContinuousGlucose Monitoring System and Methods of Use”, each of which isincorporated herein by reference.

FIG. 4 schematically shows an embodiment of an analyte sensor inaccordance with the present disclosure. This sensor embodiment includeselectrodes 401, 402 and 403 on a base 404. Electrodes (and/or otherfeatures) may be applied or otherwise processed using any suitabletechnology, e.g., chemical vapor deposition (CVD), physical vapordeposition, sputtering, reactive sputtering, printing, coating, ablating(e.g., laser ablation), painting, dip coating, etching, and the like.Materials include, but are not limited to aluminum, carbon (such asgraphite), cobalt, copper, gallium, gold, indium, iridium, iron, lead,magnesium, mercury (as an amalgam), nickel, niobium, osmium, palladium,platinum, rhenium, rhodium, selenium, silicon (e.g., dopedpolycrystalline silicon), silver, tantalum, tin, titanium, tungsten,uranium, vanadium, zinc, zirconium, mixtures thereof, and alloys,oxides, or metallic compounds of these elements.

The sensor may be wholly implantable in a user or may be configured sothat only a portion is positioned within (internal) a user and anotherportion outside (external) a user. For example, the sensor 400 mayinclude a portion positionable above a surface of the skin 410, and aportion positioned below the skin. In such embodiments, the externalportion may include contacts (connected to respective electrodes of thesecond portion by traces) to connect to another device also external tothe user such as a transmitter unit. While the embodiment of FIG. 4shows three electrodes side-by-side on the same surface of base 404,other configurations are contemplated, e.g., fewer or greaterelectrodes, some or all electrodes on different surfaces of the base orpresent on another base, some or all electrodes stacked together,electrodes of differing materials and dimensions, etc.

FIG. 5A shows a perspective view of an embodiment of an electrochemicalanalyte sensor 500 having a first portion (which in this embodiment maybe characterized as a major portion) positionable above a surface of theskin 510, and a second portion (which in this embodiment may becharacterized as a minor portion) that includes an insertion tip 530positionable below the skin, e.g., penetrating through the skin andinto, e.g., the subcutaneous space 520, in contact with the user'sbiofluid such as interstitial fluid. Contact portions of a workingelectrode 501, a reference electrode 502, and a counter electrode 503are positioned on the portion of the sensor 500 situated above the skinsurface 510. Working electrode 501, a reference electrode 502, and acounter electrode 503 are shown at the second section and particularlyat the insertion tip 530. Traces may be provided from the electrode atthe tip to the contact, as shown in FIG. 5A. It is to be understood thatgreater or fewer electrodes may be provided on a sensor. For example, asensor may include more than one working electrode and/or the counterand reference electrodes may be a single counter/reference electrode,etc.

FIG. 5B shows a cross sectional view of a portion of the sensor 500 ofFIG. 5A. The electrodes 501, 502 and 503, of the sensor 500 as well asthe substrate and the dielectric layers are provided in a layeredconfiguration or construction. For example, as shown in FIG. 5B, in oneaspect, the sensor 500 (such as the sensor unit 101 FIG. 1), includes asubstrate layer 504, and a first conducting layer 501 such as carbon,gold, etc., disposed on at least a portion of the substrate layer 504,and which may provide the working electrode. Also shown disposed on atleast a portion of the first conducting layer 501 is a sensing layer508.

A first insulation layer such as a first dielectric layer 505 isdisposed or layered on at least a portion of the first conducting layer501, and further, a second conducting layer 509 may be disposed orstacked on top of at least a portion of the first insulation layer (ordielectric layer) 505. As shown in FIG. 5B, the second conducting layer509 may provide the reference electrode 502, and in one aspect, mayinclude a layer of silver/silver chloride (Ag/AgCl), gold, etc.

A second insulation layer 506 such as a dielectric layer in oneembodiment may be disposed or layered on at least a portion of thesecond conducting layer 509. Further, a third conducting layer 503 mayprovide the counter electrode 503. It may be disposed on at least aportion of the second insulation layer 506. Finally, a third insulationlayer may be disposed or layered on at least a portion of the thirdconducting layer 503. In this manner, the sensor 500 may be layered suchthat at least a portion of each of the conducting layers is separated bya respective insulation layer (for example, a dielectric layer). Theembodiment of FIGS. 5A and 5B show the layers having different lengths.Some or all of the layers may have the same or different lengths and/orwidths.

In certain embodiments, some or all of the electrodes 501, 502, 503 maybe provided on the same side of the substrate 504 in the layeredconstruction as described above, or alternatively, may be provided in aco-planar manner such that two or more electrodes may be positioned onthe same plane (e.g., side-by side (e.g., parallel) or angled relativeto each other) on the substrate 504. For example, co-planar electrodesmay include a suitable spacing there between and/or include dielectricmaterial or insulation material disposed between the conductinglayers/electrodes. Furthermore, in certain embodiments one or more ofthe electrodes 501, 502, 503 may be disposed on opposing sides of thesubstrate 504. In such embodiments, contact pads may be on the same ordifferent sides of the substrate. For example, an electrode may be on afirst side and its respective contact may be on a second side, e.g., atrace connecting the electrode and the contact may traverse through thesubstrate.

As noted above, analyte sensors may include an analyte-responsive enzymeto provide a sensing component or sensing layer. Some analytes, such asoxygen, can be directly electrooxidized or electroreduced on a sensor,and more specifically at least on a working electrode of a sensor. Otheranalytes, such as glucose and lactate, require the presence of at leastone electron transfer agent and/or at least one catalyst to facilitatethe electrooxidation or electroreduction of the analyte. Catalysts mayalso be used for those analyte, such as oxygen, that can be directlyelectrooxidized or electroreduced on the working electrode. For theseanalytes, each working electrode includes a sensing layer (see forexample sensing layer 408 of FIG. 5B) proximate to or on a surface of aworking electrode. In many embodiments, a sensing layer is formed nearor on only a small portion of at least a working electrode.

The sensing layer includes one or more components designed to facilitatethe electrochemical oxidation or reduction of the analyte. The sensinglayer may include, for example, a catalyst to catalyze a reaction of theanalyte and produce a response at the working electrode, an electrontransfer agent to transfer electrons between the analyte and the workingelectrode (or other component), or both.

A variety of different sensing layer configurations may be used. Incertain embodiments, the sensing layer is deposited on the conductivematerial of a working electrode. The sensing layer may extend beyond theconductive material of the working electrode. In some cases, the sensinglayer may also extend over other electrodes, e.g., over the counterelectrode and/or reference electrode (or counter/reference is provided).

A sensing layer that is in direct contact with the working electrode maycontain an electron transfer agent to transfer electrons directly orindirectly between the analyte and the working electrode, and/or acatalyst to facilitate a reaction of the analyte. For example, aglucose, lactate, or oxygen electrode may be formed having a sensinglayer which contains a catalyst, such as glucose oxidase, lactateoxidase, or laccase, respectively, and an electron transfer agent thatfacilitates the electrooxidation of the glucose, lactate, or oxygen,respectively.

In other embodiments the sensing layer is not deposited directly on theworking electrode. Instead, the sensing layer may be spaced apart fromthe working electrode, and separated from the working electrode, e.g.,by a separation layer. A separation layer may include one or moremembranes or films or a physical distance. In addition to separating theworking electrode from the sensing layer the separation layer may alsoact as a mass transport limiting layer and/or an interferent eliminatinglayer and/or a biocompatible layer.

In certain embodiments which include more than one working electrode,one or more of the working electrodes may not have a correspondingsensing layer, or may have a sensing layer which does not contain one ormore components (e.g., an electron transfer agent and/or catalyst)needed to electrolyze the analyte. Thus, the signal at this workingelectrode may correspond to background signal, which may be removed fromthe analyte signal obtained from one or more other working electrodesthat are associated with fully-functional sensing layers by, forexample, subtracting the signal.

In certain embodiments, the sensing layer includes one or more electrontransfer agents. Electron transfer agents that may be employed areelectroreducible and electrooxidizable ions or molecules having redoxpotentials that are a few hundred millivolts above or below the redoxpotential of the standard calomel electrode (SCE). The electron transferagent may be organic, organometallic, or inorganic. Examples of organicredox species are quinones and species that in their oxidized state havequinoid structures, such as Nile blue and indophenol. Examples oforganometallic redox species are metallocenes such as ferrocene.Examples of inorganic redox species are hexacyanoferrate (III),ruthenium hexamine etc.

In certain embodiments, electron transfer agents have structures orcharges which prevent or substantially reduce the diffusional loss ofthe electron transfer agent during the period of time that the sample isbeing analyzed. For example, electron transfer agents include, but arenot limited to, a redox species, e.g., bound to a polymer which can inturn be disposed on or near the working electrode. The bond between theredox species and the polymer may be covalent, coordinative, or ionic.Although any organic, organometallic or inorganic redox species may bebound to a polymer and used as an electron transfer agent, in certainembodiments, the redox species is a transition metal compound orcomplex, e.g., osmium, ruthenium, iron, and cobalt compounds orcomplexes. It will be recognized that many redox species described foruse with a polymeric component may also be used, without a polymericcomponent.

One type of polymeric electron transfer agent contains a redox speciescovalently bound in a polymeric composition. An example of this type ofmediator is poly(vinylferrocene). Another type of electron transferagent contains an ionically-bound redox species. This type of mediatormay include a charged polymer coupled to an oppositely charged redoxspecies. Examples of this type of mediator include a negatively chargedpolymer coupled to a positively charged redox species such as an osmiumor ruthenium polypyridyl cation. Another example of an ionically-boundmediator is a positively charged polymer such as quaternizedpoly(4-vinyl pyridine) or poly(1-vinyl imidazole) coupled to anegatively charged redox species such as ferricyanide or ferrocyanide.In other embodiments, electron transfer agents include a redox speciescoordinatively bound to a polymer. For example, the mediator may beformed by coordination of an osmium or cobalt 2,2′-bipyridyl complex topoly(1-vinyl imidazole) or poly(4-vinyl pyridine).

Suitable electron transfer agents are osmium transition metal complexeswith one or more ligands, each ligand having a nitrogen-containingheterocycle such as 2,2′-bipyridine, 1,10-phenanthroline, 1-methyl,2-pyridyl biimidazole, or derivatives thereof. The electron transferagents may also have one or more ligands covalently bound in a polymer,each ligand having at least one nitrogen-containing heterocycle, such aspyridine, imidazole, or derivatives thereof. One example of an electrontransfer agent includes (a) a polymer or copolymer having pyridine orimidazole functional groups and (b) osmium cations complexed with twoligands, each ligand containing 2,2′-bipyridine, 1,10-phenanthroline, orderivatives thereof, the two ligands not necessarily being the same.Some derivatives of 2,2′-bipyridine for complexation with the osmiumcation include, but are not limited to 4,4′-dimethyl-2,2′-bipyridine andmono-, di-, and polyalkoxy-2,2′-bipyridines, such as4,4′-dimethoxy-2,2′-bipyridine. Derivatives of 1,10-phenanthroline forcomplexation with the osmium cation include, but are not limited to4,7-dimethyl-1,10-phenanthroline and mono, di-, andpolyalkoxy-1,10-phenanthrolines, such as4,7-dimethoxy-1,10-phenanthroline. Polymers for complexation with theosmium cation include, but are not limited to polymers and copolymers ofpoly(l-vinyl imidazole) (referred to as “PVI”) and poly(4-vinylpyridine) (referred to as “PVP”). Suitable copolymer substituents ofpoly(1-vinyl imidazole) include acrylonitrile, acrylamide, andsubstituted or quaternized N-vinyl imidazole, e.g., electron transferagents with osmium complexed to a polymer or copolymer of poly(1-vinylimidazole).

Embodiments may employ electron transfer agents having a redox potentialranging from about −200 mV to about +200 mV versus the standard calomelelectrode (SCE). The sensing layer may also include a catalyst which iscapable of catalyzing a reaction of the analyte. The catalyst may also,in some embodiments, act as an electron transfer agent. One example of asuitable catalyst is an enzyme which catalyzes a reaction of theanalyte. For example, a catalyst, such as a glucose oxidase, glucosedehydrogenase (e.g., pyrroloquinoline quinone (PQQ), dependent glucosedehydrogenase, flavine adenine dinucleotide (FAD), or nicotinamideadenine dinucleotide (NAD) dependent glucose dehydrogenase), may be usedwhen the analyte of interest is glucose. A lactate oxidase or lactatedehydrogenase may be used when the analyte of interest is lactate.Laccase may be used when the analyte of interest is oxygen or whenoxygen is generated or consumed in response to a reaction of theanalyte.

The sensing layer may also include a catalyst which is capable ofcatalyzing a reaction of the analyte. The catalyst may also, in someembodiments, act as an electron transfer agent. One example of asuitable catalyst is an enzyme which catalyzes a reaction of theanalyte. For example, a catalyst, such as a glucose oxidase, glucosedehydrogenase (e.g., pyrroloquinoline quinone (PQQ), dependent glucosedehydrogenase or oligosaccharide dehydrogenase, flavine adeninedinucleotide (FAD) dependent glucose dehydrogenase, nicotinamide adeninedinucleotide (NAD) dependent glucose dehydrogenase), may be used whenthe analyte of interest is glucose. A lactate oxidase or lactatedehydrogenase may be used when the analyte of interest is lactate.Laccase may be used when the analyte of interest is oxygen or whenoxygen is generated or consumed in response to a reaction of theanalyte. In certain embodiments, a catalyst may be attached to apolymer, cross linking the catalyst with another electron transfer agent(which, as described above, may be polymeric). A second catalyst mayalso be used in certain embodiments. This second catalyst may be used tocatalyze a reaction of a product compound resulting from the catalyzedreaction of the analyte. The second catalyst may operate with anelectron transfer agent to electrolyze the product compound to generatea signal at the working electrode. Alternatively, a second catalyst maybe provided in an interferent-eliminating layer to catalyze reactionsthat remove interferents.

Certain embodiments include a Wired Enzyme™ sensing layer (AbbottDiabetes Care) that works at a gentle oxidizing potential, e.g., apotential of about +40 mV. This sensing layer uses an osmium (Os)-basedmediator designed for low potential operation and is stably anchored ina polymeric layer. Accordingly, in certain embodiments the sensingelement is a redox active component that includes (1) Osmium-basedmediator molecules attached by stable (bidente) ligands anchored to apolymeric backbone, and (2) glucose oxidase enzyme molecules. These twoconstituents are crosslinked together.

A mass transport limiting layer (not shown), e.g., an analyte fluxmodulating layer, may be included with the sensor to act as adiffusion-limiting barrier to reduce the rate of mass transport of theanalyte, for example, glucose or lactate, into the region around theworking electrodes. The mass transport limiting layers are useful inlimiting the flux of an analyte to a working electrode in anelectrochemical sensor so that the sensor is linearly responsive over alarge range of analyte concentrations and is easily calibrated. Masstransport limiting layers may include polymers and may be biocompatible.A mass transport limiting layer may provide many functions, e.g.,biocompatibility and/or interferent-eliminating, etc.

In certain embodiments, a mass transport limiting layer is a membranecomposed of crosslinked polymers containing heterocyclic nitrogengroups, such as polymers of polyvinylpyridine and polyvinylimidazole.Embodiments also include membranes that are made of a polyurethane, orpolyether urethane, or chemically related material, or membranes thatare made of silicone, and the like.

A membrane may be formed by crosslinking in situ a polymer, modifiedwith a zwitterionic moiety, a non-pyridine copolymer component, andoptionally another moiety that is either hydrophilic or hydrophobic,and/or has other desirable properties, in an alcohol-buffer solution.The modified polymer may be made from a precursor polymer containingheterocyclic nitrogen groups. For example, a precursor polymer may bepolyvinylpyridine or polyvinylimidazole. Optionally, hydrophilic orhydrophobic modifiers may be used to “fine-tune” the permeability of theresulting membrane to an analyte of interest. Optional hydrophilicmodifiers, such as poly(ethylene glycol), hydroxyl or polyhydroxylmodifiers, may be used to enhance the biocompatibility of the polymer orthe resulting membrane.

A membrane may be formed in situ by applying an alcohol-buffer solutionof a crosslinker and a modified polymer over an enzyme-containingsensing layer and allowing the solution to cure for about one to twodays or other appropriate time period. The crosslinker-polymer solutionmay be applied to the sensing layer by placing a droplet or droplets ofthe solution on the sensor, by dipping the sensor into the solution, orthe like. Generally, the thickness of the membrane is controlled by theconcentration of the solution, by the number of droplets of the solutionapplied, by the number of times the sensor is dipped in the solution, orby any combination of these factors. A membrane applied in this mannermay have any combination of the following functions: (1) mass transportlimitation, i.e., reduction of the flux of analyte that can reach thesensing layer, (2) biocompatibility enhancement, or (3) interferentreduction.

The electrochemical sensors may employ any suitable measurementtechnique. For example, may detect current or may employ potentiometry.Techniques may include, but are not limited to amperometry, coulometry,voltammetry. In some embodiments, sensing systems may be optical,colorimetric, and the like.

In certain embodiments, the sensing system detects hydrogen peroxide toinfer glucose levels. For example, a hydrogen peroxide-detecting sensormay be constructed in which a sensing layer includes enzyme such asglucose oxides, glucose dehydrogenase, or the like, and is positionedproximate to the working electrode. The sending layer may be covered bya membrane that is selectively permeable to glucose. Once the glucosepasses through the membrane, it is oxidized by the enzyme and reducedglucose oxidase can then be oxidized by reacting with molecular oxygento produce hydrogen peroxide.

Certain embodiments include a hydrogen peroxide-detecting sensorconstructed from a sensing layer prepared by crosslinking two componentstogether, for example: (1) a redox compound such as a redox polymercontaining pendent Os polypyridyl complexes with oxidation potentials ofabout +200 mV vs. SCE, and (2) periodate oxidized horseradish peroxidase(HRP). Such a sensor functions in a reductive mode; the workingelectrode is controlled at a potential negative to that of the Oscomplex, resulting in mediated reduction of hydrogen peroxide throughthe HRP catalyst.

In another example, a potentiometric sensor can be constructed asfollows. A glucose-sensing layer is constructed by crosslinking together(1) a redox polymer containing pendent Os polypyridyl complexes withoxidation potentials from about −200 mV to +200 mV vs. SCE, and (2)glucose oxidase. This sensor can then be used in a potentiometric mode,by exposing the sensor to a glucose containing solution, underconditions of zero current flow, and allowing the ratio ofreduced/oxidized Os to reach an equilibrium value. The reduced/oxidizedOs ratio varies in a reproducible way with the glucose concentration,and will cause the electrode's potential to vary in a similar way.

A sensor may also include an active agent such as an anticlotting and/orantiglycolytic agent(s) disposed on at least a portion of a sensor thatis positioned in a user. An anticlotting agent may reduce or eliminatethe clotting of blood or other body fluid around the sensor,particularly after insertion of the sensor. Examples of usefulanticlotting agents include heparin and tissue plasminogen activator(TPA), as well as other known anticlotting agents. Embodiments mayinclude an antiglycolytic agent or precursor thereof. Examples ofantiglycolytic agents are glyceraldehyde, fluoride ion, and mannose.

Sensors may be configured to require no system calibration or no usercalibration. For example, a sensor may be factory calibrated and neednot require further calibrating. In certain embodiments, calibration maybe required, but may be done without user intervention, i.e., may beautomatic. In those embodiments in which calibration by the user isrequired, the calibration may be according to a predetermined scheduleor may be dynamic, i.e., the time for which may be determined by thesystem on a real-time basis according to various factors, such as butnot limited to glucose concentration and/or temperature and/or rate ofchange of glucose, etc.

Calibration may be accomplished using an in vitro test strip (or otherreference), e.g., a small sample test strip such as a test strip thatrequires less than about 1 microliter of sample (for example FreeStyle®blood glucose monitoring test strips from Abbott Diabetes Care Inc.).For example, test strips that require less than about 1 nanoliter ofsample may be used. In certain embodiments, a sensor may be calibratedusing only one sample of body fluid per calibration event. For example,a user need only lance a body part one time to obtain sample for acalibration event (e.g., for a test strip), or may lance more than onetime within a short period of time if an insufficient volume of sampleis firstly obtained. Embodiments include obtaining and using multiplesamples of body fluid for a given calibration event, where glucosevalues of each sample are substantially similar. Data obtained from agiven calibration event may be used independently to calibrate orcombined with data obtained from previous calibration events, e.g.,averaged including weighted averaged, etc., to calibrate. In certainembodiments, a system need only be calibrated once by a user, whererecalibration of the system is not required.

Analyte systems may include an optional alarm system that, e.g., basedon information from a processor, warns the patient of a potentiallydetrimental condition of the analyte. For example, if glucose is theanalyte, an alarm system may warn a user of conditions such ashypoglycemia and/or hyperglycemia and/or impending hypoglycemia, and/orimpending hyperglycemia. An alarm system may be triggered when analytelevels approach, reach or exceed a threshold value. An alarm system mayalso, or alternatively, be activated when the rate of change, oracceleration of the rate of change, in analyte level increase ordecrease approaches, reaches or exceeds a threshold rate oracceleration. A system may also include system alarms that notify a userof system information such as battery condition, calibration, sensordislodgment, sensor malfunction, etc. Alarms may be, for example,auditory and/or visual. Other sensory-stimulating alarm systems may beused including alarm systems which heat, cool, vibrate, or produce amild electrical shock when activated.

The subject disclosure also includes sensors used in sensor-based drugdelivery systems. The system may provide a drug to counteract the highor low level of the analyte in response to the signals from one or moresensors. Alternatively, the system may monitor the drug concentration toensure that the drug remains within a desired therapeutic range. Thedrug delivery system may include one or more (e.g., two or more)sensors, a processing unit such as a transmitter, a receiver/displayunit, and a drug administration system. In some cases, some or allcomponents may be integrated in a single unit. A sensor-based drugdelivery system may use data from the one or more sensors to providenecessary input for a control algorithm/mechanism to adjust theadministration of drugs, e.g., automatically or semi-automatically. Asan example, a glucose sensor may be used to control and adjust theadministration of insulin from an external or implanted insulin pump.

In certain circumstances, the analyte sensor experiences a sudden dropin sensitivity (defined, for example, as the amount of electrical signalgenerated by the sensor for every unit of glucose in the interstitialfluid) followed by a signal recovery, generally referred to as signaldropouts. The signal dropouts may be attributed to attenuation of theglucose flux by for example occlusion of the working electrode surfaceof the analyte sensor due to, for example, presence of gas bubbles,contact with tissue (with or without trauma from sensor insertion),contact with cells or partial pull out or withdrawal of the sensor fromthe initial position. Generally, such signal dropouts may trigger falsehypoglycemic alarm leads to misinforming the user or the patient of suchcondition.

Accordingly, in one aspect, the analyte sensor may be configured tomitigate the sensitivity attenuation due to signal dropouts, forexample, based on signal processing using multiple working electrodes ofthe analyte sensor. More specifically, in one aspect, the analyte sensormay be configured with two working electrodes, each with a separatesensing layer, and where the sensing layer of each working electrode isseparated by a predetermined distance on the sensor body. For example,in one aspect, the analyte sensor may include a first working electrodewith a first sensing layer disposed substantially at the distal tip ofthe sensor and positioned, for example, in the interstitial fluid of theuser.

The analyte sensor may additionally include a second working electrode(either on the same or opposing side of the sensor) with a secondsensing layer disposed at a predetermined distance from the firstsensing layer of the first working electrode at the distal tip of theanalyte sensor. For example, the second sensing layer of the secondworking electrode of the analyte sensor may be positioned in the dermallayer of the patient, or alternatively, in the interstitial layer butseparated from the first sensing layer of the first working electrode bya predetermined distance within the interstitial layer.

In this manner, in one aspect, by providing multiple working electrodesin the analyte sensor each having a separate sensing layer, when signalsfrom one working electrode is attenuated, for example, due to dropoutconditions resulting from presence of occluding material around thesensing layer of the electrode, the other working electrode may notexperience the same or similar dropout conditions. For example, in thecase where the sensor is partially withdrawn or dislodged, the signalsfrom the working electrode positioned away from the distal tip of thesensor may be attenuated due to loss of contact with the interstitialfluid, while the working electrode with sensing layer positionedsubstantially at the distal tip of the sensor may be retained, even withthe dislodging, in the interstitial fluid, and thus the signal from thisworking electrode may not experience dropout conditions, and thusattenuation mitigated.

On the other hand, in cases where the distal tip of the sensor ispositioned near or within occluding material in the interstitial layer,the signals from the working electrode with the sensing layer at thedistal tip of the sensor may experience dropout conditions, while thesignals from the working electrode with the sensing layer at a setdistance away from the distal tip of the sensor may not be attenuated.In this manner, in one aspect, with multiple working electrodespositioned at different locations within the interstitial fluid and/orother layer under the skin (such as, for example, the dermal layer), thelikelihood of sensor sensitivity attenuation occurring at all theworking electrodes at the same time may be minimized, and thus, the dataprocessing unit 102 (FIG. 1) and/or the receiver unit 104/106 may beconfigured to process signals from multiple working electrodes tominimize the sensor signal attenuation or dropout conditions withoutvalid monitored glucose data.

That is, in one aspect, when the signals from one working electrode ofthe sensor are attenuated, signals from the other working electrode ofthe sensor may be relied upon to provide the corresponding monitoredglucose levels. By physically separating the distance between the two(or more) working electrodes of the sensor and their respective sensinglayer, the likelihood of both (or all) working electrodes experiencingthe signal dropout conditions at substantially the same time isminimized.

FIG. 6 is a graphical illustration of sensor sensitivity attenuationmitigation using multiple working electrodes in accordance with oneaspect of the present disclosure. Referring to FIG. 6, analyte levelsmonitored from the two working electrodes of the analyte sensor isplotted over a predetermined time period which includes a signal dropoutcondition. More specifically, signals from first working electrode 601and second working electrode 602 are shown. It can be further seen thatthe signals from the second working electrode 602 has experienced adropout condition during the time period 605 starting at approximatelyT1 to T2. During this time period, referring back to FIG. 6, the signalsfrom the first working electrode 601 has not experienced similar signalattenuation.

That is, as shown in FIG. 6, during the time period 605 ranging from T1and T2, a variation of magnitude between the two electrode signals aresubstantial. This is illustrated by the indicator 603 and 604 whichdemonstrate the difference between the analyte levels from the twoworking electrodes during the time period 605 from T1 and T2. This is incontrast to the difference between the analyte levels from the twoworking electrodes during the time period preceding time T1 and alsoduring the time period after the time T2.

In one aspect, the difference between the signal levels from the twoworking electrodes are monitored and compared each time they arereceived (for example, every minute, every 5 minutes, and so on), and acomparison between the signals from the two working electrodes areperformed. When the comparison yields a result that returns a differencein the signals from the two working electrodes that exceed apredetermined threshold level (such as, for example, but not limited to,a difference of approximately 15%), in one aspect, the less or smallersignal of the two signals from the respective working electrodes isdeclared as a dropout signal, and while the other, larger signal fromthe other of the two working electrodes is considered to be a validsignal. In this manner, referring back to FIG. 6, in one aspect, signalsfrom the second working electrode 602 are considered to be invalidduring the time period 605 ranging from time T1 and T2, and the signalfrom the first working electrode 601 is accepted as the valid signalduring this time period 605.

FIG. 7 is a graphical illustration of sensor sensitivity attenuationmitigation using multiple working electrodes in accordance with anotheraspect of the present disclosure. Referring to FIG. 7, in anotheraspect, the signals from the two working electrodes may substantiallyconcurrently experience a rapid decrease in the signal level. Indeed, asshown, signals from the first working electrode 701 and the signals fromthe second working electrode 702 during the time period 705 ranging fromtime T1 to time T2 illustrate apparent attenuation. As further shown inFIG. 7, the signals from the first working electrode 701 during thistime period 705 are not as attenuated as compared to the signals fromthe second working electrode 702 during the same time period 705.

Accordingly, when it is detected that signals from both workingelectrodes appear to experience a dropout type condition or attenuation,in one aspect, signals from both working electrodes may be consideredattenuated and invalid. Thus, no valid data or analyte level may bedisplayed or output to the user during this time period 705. On theother hand, referring again to FIG. 7, when signals from both workingelectrodes are attenuated, the difference between the magnitude of thesignals from the two working electrodes may be determined to confirmattenuation of signals from both working electrodes, or alternatively,to potentially validate one of the two signals from the two workingelectrodes by determining the rate of change of the signal levels.

That is, in one aspect, when the monitored signals from both workingelectrodes experience a dropout type condition, for example, as shownsubstantially at time T1, a rate of change of the signal level isdetermined based on the signals from the working electrode that isexperiencing relatively less dropout (signals from the first workingelectrode 701 in FIG. 7). The determined rate of change of the signallevel in one aspect, is compared to a predetermined threshold level(such as exceeding 0.5 mg/dL/minute, or any other suitable thresholdlevel).

When the rate of the change of the signal level determined does notexceed the predetermined threshold level, in one aspect, the signalsfrom the first working electrode 701 are considered validated andacceptable. That is, even when the signals from the electrodes areundergoing varying degrees of attenuation, by performing a rate ofchange analysis, it may be determined that the signal attenuation of thelesser of the two signals from the respective working electrodes 701,702 is attributable to a decline in the corresponding glucose level(rather than an attenuation of the signal itself due to occlusion orsome other undesirable condition indicating a false positive potentialhypoglycemic condition).

In a further aspect, analysis or processing of signals from two or moreworking electrodes may also include configurations in which the largerof the two signals at any given time period is considered as validoutput signal of the sensor. Alternatively, the signals from the two ormore working electrodes may be averaged (for example, when the absolutedifference between the two signals is less than a predeterminedthreshold indicating absence of dropout conditions), weighted based on apredetermined criteria, to determine the corresponding output signal ofthe analyte sensor.

In another aspect, the shape and/or size of the working electrode may bemodified to minimize sensitivity attenuation of the sensor. For example,signal attenuation may result from partial occlusion or blockage of thesensing layer of the sensor working electrode. Accordingly, for anocclusion of a predetermined size, shape and/or location, the resultingsignal attenuation may be less for a sensor having a larger workingelectrode with the sensing layer. Similarly, smaller electrodes mayincrease the magnitude of the potential signal attenuation, if present,and resulting in easier detection of occlusion or the cause of thesignal attenuation.

In this manner, in one embodiment, the analyte sensor may be configuredto include one relatively large working electrode, and one or morerelatively smaller working electrodes that are configured to provideindications that the signals from the relatively large working electrodemay be attenuated. By way of an example, FIG. 8C illustrates oneembodiment of a sensor working electrode layout including a largeworking electrode with sensing layer 801 which is surrounded by multiple(in this case, seven) smaller working electrodes 802 a, 802 b, 802 c, 80d, 802 e, 802 f, and 802 g, each of which are electrically connected toeach other. When the sensor is positioned with the working electrodes801 and 802 a-802 g substantially in fluid contact with the interstitialfluid, presence of occlusion or other signal attenuation condition ofthe signals from the working electrode 801 may be more easily detectedby one or more of the working electrodes 802 a-802 g, while the largerworking electrode 801 may be configured to provide the output sensorsignals corresponding to the monitored glucose levels.

Furthermore, in still another aspect, the shape of the working electrodemay be configured to minimize signal attenuation or increase thedetectability of dropout conditions. For example, as shown in FIG. 8A,the working electrode 810 may be shaped in a triangular shape with thetip portion 811 of the triangular shaped working electrode 810positioned substantially at the distal end of the analyte sensor. Thisconfiguration may minimize signal attenuation by reducing the size ofthe working electrode at the distal tip of the sensor when occlusionspredominantly occur in this area.

FIG. 8B illustrates another embodiment of analyte sensor electrodegeometry for sensitivity attenuation mitigation in accordance withaspects of the present disclosure. Referring to FIG. 8B, two workingelectrodes 820, 830 are shown, each having a substantially triangularshape in the manner shown. In this embodiment, when the occlusioncausing signal dropout occurs near the distal end of the sensor wherethe tip portion 821 of the working electrode 820 is located (that is,for example, the occlusion is slowly moving its way up the sensor fromthe distal tip), working electrode 820 may be configured to output thesensor signal, while the working electrode 830 may be configured todetect the presence of the occlusion resulting in the signalattenuation. That is, in one aspect, the larger end of the triangularshaped working electrode 830 positioned proximate to the tip portion 821of the working electrode 820, given its size, may detect signalattenuation or occlusion more easily, as compared to the tip portion 821of the working electrode 820 which is relatively smaller.

In another aspect, in the case where occlusion (such as tissue mass orsome blockage) may migrate across the two working electrodes of theanalyte sensor, the signals from one working electrode may attenuatebefore the signals in the other working electrode are attenuated. Inthis case, a temporal difference between the signals from the twoworking electrodes exceeding a predetermined threshold may indicate thatthe analyte sensor signal dropout is occurring. In other words, thesignals from the first working electrode that the occlusion edge hascome into contact, migrating over it may experience signal attenuationbefore the same or similar degree of signal attenuation is experiencedby the second working electrode.

Furthermore, a similar determination may be made upon signal recoveryfrom a dropout, where the recovery occurs at a different time for oneworking electrode versus the other working electrode. Also, it is to benoted that each electrode may have a different time lag response toabrupt changes in glucose and that the specific lag may be taken intoconsideration for these comparisons or determinations.

As discussed above, other geometries, shapes and sizes may becontemplated within the scope of the present disclosure includingmultiple working electrodes with predetermined positioning of thesensing layer on the working sensor body to mitigate sensor signalattenuation.

FIGS. 9A-9B illustrate embodiments of analyte sensor electrode geometryfor sensitivity attenuation mitigation in accordance with furtheraspects of the present disclosure. Referring to FIG. 9A, geometry ofworking electrode 910 is shown to include multiple sensing areas 912 a,912 b, 912 c, 912 d, which are electrically coupled to the contact orconnector 911. Accordingly, when the occlusion edge moves vertically inthe direction shown by arrow 913, the sensing areas 912 a, 912 b, 912 c,and 912 d will sequentially come into contact with the occlusion edge,and thus the working electrode signals will display sudden changes ordrops in sensitivity in, for example, a cascading or in a step wisemanner. That is, as the occlusion moves over the working electrode 910and covers or blocks the sensing areas 912 a, 912 b, 912 c, and 912 d,with each sensing area blocked, the corresponding signal from the sensordrops rapidly. Accordingly, signals that display such characteristics orprofiles may be associated with actual sensor sensitivity attenuation,rather than a false positive indication of a potential signal dropout.

Referring to FIG. 9B, as shown, in a further aspect, two workingelectrodes 920, 930 each with multiple sensing areas 921 a, 921 b, 921c, and 931 a, 931 b, 931 c are provided on the analyte sensor withdifferent orientations. As discussed above, analyte sensor havingmultiple working electrodes, each with multiple sensing areas may beconfigured to form sensitive areas for occlusion detection foridentifying signal attenuation. While the embodiments shown anddescribed above in conjunction with the figures illustrate particularnumber of working electrodes with specific number of sensing areas, aswell as orientation, geometry and position, within the scope of thepresent disclosure, other configurations including the number of workingelectrodes, the number of sensing areas for each working electrode, theorientation, geometry and position of each working electrode and eachsensing area are contemplated for analyte sensor.

In one embodiment, a method may comprise, receiving a first signal froma first working electrode of a glucose sensor positioned at a firstpredetermined position under the skin layer, receiving a second signalfrom a second working electrode of the glucose sensor positioned at asecond predetermined position under the skin layer, the second signalreceived substantially contemporaneous to receiving the first signal,detecting a dropout in the signal level associated with one of the firstor second signals, comparing the first signal and the second signal todetermine a variation between the first and second signals, andconfirming one of the first or second signals as a valid glucose sensorsignal output when the determined variation between the first and thesecond signals is less than a predetermined threshold level.

In one aspect, the predetermined threshold level may be approximately15%.

In another aspect, the valid glucose sensor signal may be the largersignal between the first signal and the second signal.

Moreover, the other one of the first or second signals may be confirmedas an invalid signal.

Furthermore, when the variation between the first and the second signalsexceeds the predetermined threshold level, confirming both of the firstor second signals as invalid sensor output signal.

Furthermore, when the variation between the first and the second signalexceeds the predetermined threshold level, performing a rate of changedetermination of signals from one of the first or the second workingelectrode, and confirming one of the first or the second signals as thevalid glucose sensor signal when the determined rate of change level isless than a predetermined threshold level.

Moreover, the predetermined threshold level used to compare the rate ofchange level may include approximately 0.5 mg/dL per minute.

Moreover, the rate of change determination may be performed on signalsfrom the one of the first or the second working electrodes that islarger in magnitude.

Furthermore, when the determined rate of change level is greater thanthe predetermined threshold level, confirming both of the first and thesecond signals from the first and the second working electrodes,respectively as invalid sensor signals.

In yet another aspect, the first predetermined position may be separatedby a predetermined distance from the second predetermined position.

In another aspect, at least a portion of the first working electrode maybe in fluid contact with an interstitial fluid, and further, wherein thesecond working electrode may include at least a portion in fluid contactwith the interstitial fluid, and further, wherein the firstpredetermined position and the second predetermined position may beseparated by a predetermined distance.

In yet another aspect, the first predetermined position may include atleast a portion of the first working electrode in fluid contact with aninterstitial fluid, and further, wherein the second predeterminedposition may include substantially the entire second working electrodenot in fluid contact with the interstitial fluid.

In still another aspect, the first working electrode may be disposed ona first surface of the glucose sensor, and further, wherein the secondworking electrode may be disposed on a second surface of the glucosesensor.

Furthermore, the first surface and the second surface may be co-planar.

Furthermore still, the first surface and the second surface may be onopposing sides of the glucose sensor.

In one embodiment, an apparatus may comprise a data communicationinterface, one or more processors coupled to the data communicationinterface, and a memory storing instructions which, when executed by theone or more processors, receives a first signal from a first workingelectrode of a glucose sensor positioned at a first predeterminedposition under the skin layer, receives a second signal from a secondworking electrode of the glucose sensor positioned at a secondpredetermined position under the skin layer, the second signal receivedsubstantially contemporaneous to receiving the first signal, detects adropout in the signal level associated with one of the first or secondsignals, compares the first signal and the second signal to determine avariation between the first and second signals, and confirming one ofthe first or second signals as a valid glucose sensor signal output whenthe determined variation between the first and the second signals isless than a predetermined threshold level.

In one aspect, when the variation between the first and the secondsignals exceeds the predetermined threshold level, the memory storinginstructions which, when executed by the one or more processors, mayconfirm both of the first or second signals as invalid sensor outputsignals.

In another aspect, when the variation between the first and the secondsignal exceeds the predetermined threshold level, the memory storinginstructions which, when executed by the one or more processors, mayperform a rate of change determination of signals from one of the firstor the second working electrode, and may confirm one of the first or thesecond signals as the valid glucose sensor signal when the determinedrate of change level is less than a predetermined threshold level.

Furthermore, when the determined rate of change level is greater thanthe predetermined threshold level, the memory storing instructionswhich, when executed by the one or more processors, may confirm both ofthe first and the second signals from the first and the second workingelectrodes, respectively as invalid sensor signals.

In one embodiment, an apparatus may comprise means for receiving a firstsignal from a first working electrode of a glucose sensor positioned ata first predetermined position under the skin layer, means for receivinga second signal from a second working electrode of the glucose sensorpositioned at a second predetermined position under the skin layer, thesecond signal received substantially contemporaneous to receiving thefirst signal, means for detecting a dropout in the signal levelassociated with one of the first or second signals, means for comparingthe first signal and the second signal to determine a variation betweenthe first and second signals, and means for confirming one of the firstor second signals as a valid glucose sensor signal output when thedetermined variation between the first and the second signals is lessthan a predetermined threshold level.

Various other modifications and alterations in the structure and methodof operation of this present disclosure will be apparent to thoseskilled in the art without departing from the scope and spirit of thepresent disclosure. Although the present disclosure has been describedin connection with specific preferred embodiments, it should beunderstood that the present disclosure as claimed should not be undulylimited to such specific embodiments. It is intended that the followingclaims define the scope of the present disclosure and that structuresand methods within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. An apparatus, comprising: a data communicationinterface; one or more processors coupled to the data communicationinterface; and a memory storing instructions which, when executed by theone or more processors, receives a first signal from a first workingelectrode of a glucose sensor positioned at a first predeterminedposition under a skin layer, receives a second signal from a secondworking electrode of the glucose sensor positioned at a secondpredetermined position under the skin layer, the second signal receivedcontemporaneously to receiving the first signal, detects a dropout in asignal level associated with one of the first signal or the secondsignal, compares the first signal and the second signal to determine avariation between the first signal and the second signal in response todetecting the dropout in the signal level, and confirming the one of thefirst signal or the second signal as a valid glucose sensor signal whenthe determined variation between the first signal and the second signalis less than a predetermined threshold level.
 2. The apparatus of claim1, wherein when the variation between the first signal and the secondsignal exceeds the predetermined threshold level, the memory storinginstructions which, when executed by the one or more processors,confirms both of the first signal or the second signal as invalid sensoroutput signals.
 3. The apparatus of claim 1, wherein when the variationbetween the first signal and the second signal exceeds the predeterminedthreshold level, the memory storing instructions which, when executed bythe one or more processors, performs a rate of change determination ofsignals from one of the first working electrode or the second workingelectrode, and confirms the one of the first signal or the second signalas the valid glucose sensor signal when the determined rate of changelevel is less than a predetermined rate threshold level.
 4. Theapparatus of claim 3, wherein, when the determined rate of change levelis greater than the predetermined rate threshold level, the memorystoring instructions which, when executed by the one or more processors,confirms both of the first signal and the second signal from the firstworking electrode and the second working electrode, respectively asinvalid sensor signals.
 5. An apparatus, comprising: means for receivinga first signal from a first working electrode of a glucose sensorpositioned at a first predetermined position under a skin layer; meansfor receiving a second signal from a second working electrode of theglucose sensor positioned at a second predetermined position under theskin layer, the second signal received contemporaneously to receivingthe first signal; means for detecting a dropout in a signal levelassociated with one of the first signal or the second signal; means forcomparing the first signal and the second signal to determine avariation between the first signal and the second signal in response todetecting the dropout in the signal level; and means for confirming theone of the first signal or the second signal as a valid glucose sensorsignal when the determined variation between the first signal and thesecond signal is less than a predetermined threshold level.